Mobilizing endogenous progenitor cells in the adult brain for treatment of neurodegenerative and demyelinating disease offers several advantages over transplantation of stem cells (SCs). The present project is investigating the ability of the cytokine leukemia inhibitory factor (LIF) to stimulate SC and progenitor cell production, and to direct their differentiated fates in a demyelination model. Since LIF is upregulated in response to a variety of human brain injuries and diseases, experimentally increasing the level of LIF in the adult brain serves to enhance the normal response mechanism. Elevating LIF in the adult mouse brain promotes the self-renewal of NSCs, thereby increasing the number of cells that may be available for repair. In addition, LIF stimulates oligodendrocyte progenitor cell (OPC) proliferation and promotes oligodendrocyte survival. Thus, LIF can enlarge the NSC pool as well as direct NSCs towards fates that are of potential clinical importance. (1) It is proposed to examine the efficacy of this cytokine in the cuprizone model of demyelination, in which the onset of de- and remyelination can be experimentally controlled. Preliminary results indicate that exogenous LIF can significantly increase the number of OPCs and oligodendrocytes following demyelination. (2) Preliminary results also indicate that remyelination is strongly improved by LIF treatment. To explore the possibility of LIF-driven functional recovery, a collaboration has been established to study axonal conduction. (3) How does LIF increase OPCs, oligodendrocytes and myelin? Does it act directly on each of these cell types to direct their proliferation and differentiation? Preliminary results suggest that LIF acts directly on both newly generated OPCs and oligodendrocytes. Second, since LIF also activates glial cells, which in turn may influence OPCs, we will ask whether LIF stimulates OPC proliferation by direct signaling through its receptor in OPCs by conditionally deleting the gp130 component of the LIF receptor in OPCs. Third, we will investigate whether LIF has effects on oligodendrocyte survival, differentiation, and/or myelination by removing exogenous LIF at various stages of the process. Fourth, we will examine how the normal rise of endogenous LIF that is seen in multiple sclerosis and in animal models of demyelination may affect OPC proliferation, differentiation and remyelination by assessing remyelination in the LIF knockout (KO) mouse.